Transfer of Inhaled Cannabis Into Human Breast Milk

Home , Cannabis strain

8 36 783 – 7 – , 1 PhD he plasma are rapidly metab- is most commonly smoked, OBSTETRICS & GYNECOLOGY This study documents inhaled , Heather Thompson, MS Small-to-moderate secretion of tetrahydrocannab- Cannabis sativa egalization of recreational cannabisstates use has in caused several growing unease in the medical cannabis during pregnancy and breastfeeding. The estimated dailykilogram infant per dose day. was 8CONCLUSION: micrograms per delta-9-tetrahydrocannabinolthe mother’sdelta-9-tetrahydrocannabinol breast transfer milk. werelong-term Low detected. neurobehavioral concentrationsdelta-9-tetrahydrocannabinol The effect of into of onbrain exposure is the unclear. to Mothers developing should be cautious using hours, in chronic users, it might be asinol long as into 4 breast days. milk has been reported; however, inhaled, orcontains ingested more than orally. 150 Cannabis known smoke compounds. maining concentrations in t olized in the liver. Although the elimination life is 20 (Obstet Gynecol 2018;131:783–8) DOI: 10.1097/AOG.0000000000002575 L Delta-9-tetrahydrocannabinol, the mostof psychoactive the phytocannabinoids,stored is highly lipophilic invarying and is from adiposedelta-9-tetrahydrocannabinol enters weeks the tissues plasmapartment to com- almost months. instantly forand from then Once the redistributes long(brain, pulmonary to inhaled, liver, tree and highly periods, other vascularizedtrations tissues). are Thus, tissues rather plasma brief concen- (minutes)system and concentrations central nervous slightly longer (2 hours). Re- community regarding the healththis risks associated drug, with especiallywomen. Although in cannabis pregnant isused one and of phytocannabinoid the breastfeeding most drugsstanding widely in of the thecannabis long-term world, use, neurobehavioral particularly under- inlimited effect the to of observational developing and brain, animal is data. PhD s requirements for ’ , Kathleen Rewers-Felkins, PhD 2.5%, range 0.4–8.7%). Original Research 5 by American College of Obstetricians Ó , and Thomas W. Hale, PhD , Palika Datta, MD To evaluate the transfer of delta-9- In this pilot pharmacokinetic study, breast A total of eight women were enrolled. Most Unauthorized reproduction of this article is prohibited. Copyright

and Gynecologists. Published by Wolters Kluwer Health, Inc. Raja R. Kallem, VOL. 131, NO. 5, MAY 2018 The authors did not report any© potential 2018 conflicts by of AmericanWolters interest. College Kluwer of Health, Obstetricians Inc.ISSN: and All 0029-7844/18 rights Gynecologists. reserved. Published by Corresponding author: Thomas W. Hale,Tech University PhD, Health Department Sciences of Center, Pediatrics,79106; 1400 Texas Wallace email: Boulevard, [email protected]. Amarillo TX- Financial Disclosure Texas; and Elephant Circle, Denver, Colorado. Each author has indicatedauthorship. that he or she has met the journal From the DepartmentsSchool of of Obstetrics Pharmacy, Texas and Tech Gynecology University and Health Pediatrics Sciences and Center, Amarillo, the milk such that exclusivelyan breastfeeding infants estimated ingested meancalculated of relative 2.5% infant of the dose maternal dose (the concentrations at all theNo time metabolites points were beyond detected9-tetrahydrocannabinol at time any zero. was time point. transferred Delta- into mother’s RESULTS: were occasional cannabisuser. Delta-9-tetrahydrocannabinol smokers was and detected one at low a chronic hours. Quantificationand of its delta-9-tetrahydrocannabinol metabolites inples was these performed by collected high-performance breast liquidtography chroma- milk tandem mass sam- spectrometry. weighed, analyzed, standardized strain ofone preselected cannabis dispensary, from and collectples breast milk at sam- specific time points: 20 minutes and 1, 2, and 4 exclusively breastfeedinganonymously their recruited for infants. the study.cannabis After Women discontinuing for were atobtain least a baseline 24 breast milk hours, sample, they then smoke were a pre- directed to METHODS: milk samples were collected from mothersconsumed who cannabis, regularly were 2–5 months postpartum, and tetrahydrocannabinol and itsbreast milk metabolites after intocontaining maternal 23.18% human inhalation delta-9-tetrahydrocannabinol. of 0.1 g cannabis OBJECTIVE: Teresa Baker, Transfer of Inhaled Cannabis IntoBreast Human Milk Drugs in Pregnancy:

Downloaded from http://journals.lww.com/greenjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3yRlXg5VZA8uapW+4JYnZFdyBruUyRNmhPZ0cMRUAMp2s81SR/9Xqtg== on 10/09/2020 Downloaded from http://journals.lww.com/greenjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3yRlXg5VZA8uapW+4JYnZFdyBruUyRNmhPZ0cMRUAMp2s81SR/9Xqtg== on 10/09/2020 these reports may not adequately represent concen- research activity, complete explanation that participa- trations of tetrahydrocannabinol found in breast milk tion was voluntary, and acknowledgment that submit- today with newer commercialized cannabis products.9 ting samples implied consent. Each participant also The objective of this pilot pharmacokinetic study was received a toll-free phone number and was instructed to evaluate the transfer of delta-9- to call if she desired to review the instructions, consent tetrahydrocannabinol and its metabolites into human process, or any other questions arising concerning the breast milk at 20 minutes and at 1, 2, and 4 hours after study. maternal inhalation of 0.1 g cannabis containing Once a participant indicated interest in the pro- 23.18% of delta-9-tetrahydrocannabinol. This dose ject, she was instructed to obtain a breast milk was chosen after extensively reviewing older studies collection kit, which were made available for anony- wherein an average cannabis cigarette contained mous pickup at a local community center and approximately 0.6 g of cannabis, containing approxi- included a new glass pipe, six polypropylene bottles mately 3.55% tetrahydrocannabinol. This dose for breast milk collection, freezer packs, a shipping would amount to approximately 21.3 mg of container, a shipping label void of any identifying tetrahydrocannabinol. patient information, and complete instructions on how to proceed with the study protocol. A question- MATERIALS AND METHODS naire was included, which asked about the consump- We designed this pharmacokinetic study to measure tion of cannabis such as frequency, amount, and the transfer of inhaled cannabis into human breast preferred method, and also about any other milk. Institutional review board approval for this drug use. Information about infant age and mothers’ study was obtained from Texas Tech University body weight at the time of study was also collected. Health Sciences Center (A16-3968). The participants Participants were asked to purchase a preweighed were recruited through the InfantRisk website, flyers sample of Prezidential Kush cannabis (0.1 g with posted in Colorado community lactation social media delta-9-tetrahydrocannabinol content523.18%) at sites, and word of mouth through community-based a single specified dispensary to standardize the dose breastfeeding groups. Participants were required to be and concentration of the product being studied. They 18–45 years of age, exclusively breastfeeding, 1–6 were instructed to abstain from all cannabis consump- months postpartum, smoking cannabis while breast- tion for 24 hours before the commencement of the feeding, and to have delivered at 37 weeks of gestation study. Milk samples collected just before smoking or more. Participants selected were from Denver, Col- were considered the “zero hour” sample. Participants orado area and were willing to purchase the flower of were then to place 0.1 g of cannabis into the bowl of a specific cannabis strain from a preselected Denver the provided glass pipe, light, and inhale until con- dispensary. Exclusion criteria included ingestion of sumed (equivalent to approximately three to four hits cannabis orally, other drugs of abuse, and other med- over approximately 10–20 minutes). We also advised ications or herbal products. Pregnant patients and the presence of an assistant to ensure quality of sam- women supplementing their infants with formula or pling. Using the beginning of consumption as the start solids were also excluded from this study. The study time, breast milk samples were then collected at was open from January 2017 until October 2017. 20 minutes and 1, 2, and 4 hours after inhalation. Participants’ breast milk samples were collected Mothers were advised to pump their breasts with in polypropylene vials, which were previously deter- an electric pump, mix right and left breast milk mined to not bind tetrahydrocannabinol. Before initi- samples, and decant 1–2 ounces into the proper sam- ating the study, we tested these vials by assessing ple bottle. Samples were immediately stored in the stability of delta-9-tetrahydrocannabinol by spiking freezer after each collection. On average, 2 ounces blank milk standards with known concentrations at of breast milk were collected, frozen, and mailed to different storage conditions. Thereafter the extraction our facility overnight. No compensation was given to efficiency along with estimated concentrations was study participants. The participants collected only one determined with no concentration changes observed, set of samples. Because this study did not require which demonstrated that these collection vials were comparison between groups, it did not require a null appropriate for breast milk collection. To ensure com- hypothesis or mean comparisons. We were simply plete anonymity, we waived documentation of signed quantifying the drug concentrations in the collected consent. Each participant received a complete copy of breast milk samples over time. Thereby each time the consent along with a sheet reviewing frequently interval was grouped into mean6standard error and asked questions, written explanation about the the area under the curve was used to estimate the

784 Baker et al Inhaled Cannabis in Human Breast Milk OBSTETRICS & GYNECOLOGY

Copyright Ó by American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. average dose and the relative infant dose, which is the percentage of the mother’s dose that the infant might receive daily from exposure to this drug in its mother’s breast milk when breastfeeding exclusively. Delta-9-tetrahydrocannabinol concentrations in the breast milk samples were measured using high performance liquid chromatography mass spectrometry. Milk samples were thawed and 0.1 mL was transferred to acetonitrile for protein precipitation. Internal standards (final concentration 50 ng/mL) were added to each sample and standards. The analyte and internal standards were analyzed by AB Sciex QTRAP 5500 ultrahigh-performance liquid chromatography tandem mass spectrometry and attained by tandem mass spectrometry detection Fig. 1. Linear calibration curve with correlation coefficient, r250.99. Each data point represents the average of tripli- in positive ion mode. Data were acquired by cate. multiple reaction-monitoring modes with mass tran- – Baker. Inhaled Cannabis in Human Breast Milk. Obstet Gynecol sitions as follows: m/z 315 m/z 193.2 for delta-9- 2018. tetrahydrocannabinol and similarly for internal standard m/z 395.1–m/z 213 was performed. Chromato- graphic separation was achieved on Agilent Poroshell cannabis use was from 0.025 to 1 g per day. Three column (4.6350 mm 2.7 microns) and a thermostatic study participants chose not to return the question- column compartment (40°C). The concentration of naire (Table 1). The participants reported consump- each analyte was determined from the ratio of the tion of no other medications during the time of the peak area of the drug to the peak area of its internal study other than multivitamins and probiotic supple- standard and comparison of this ratio with the calibra- ments. The median postpartum interval was 5 months tion curve that was generated from the analysis of and ranged from 3 to 5 months. blank human breast milk with known concentrations Dosage administered to each mother was calcu- of delta-9-tetrahydrocannabinol. The range for the lated based on the reported delta-9- curve constructed was 1.9–500 ng/mL with a correlation tetrahydrocannabinol content of this cannabis product coefficient of 0.99 (Fig. 1). The recoveries of analyte and in 0.1 g of cannabis. The analytical report for internal standard from human breast milk were deter- Prezidential Kush cannabis documented a delta-9- mined by comparing the peak areas of the analyte in tetrahydrocannabinol content of 23.18% or 23.18 mg spiked human breast milk samples with those of analyte per 0.1 g administered. The average concentration of spiked into the post extracted breast milk blank by adding delta-9-tetrahydrocannabinol in breast milk was 53.5 equivalent concentrations of the analyte. Percent ng/mL. The mean maximum concentration in breast recovery was calculated to be 88%. Tetrahydrocannabi- milk observed was 94 ng/mL, which occurred at 1 nol metabolites 11-OH-delta-9-tetrahydrocannabinol and hour after the consumption of the cannabis. The daily 11-Nor-9-carboxy-delta-9-tetrahydrocannabinol were also absolute infant dose was estimated as average con- determined using mass spectrometry. Chromatographic sumption multiplied by an average breast milk intake conditions were similar to delta-9-tetrahydrocannabinol of 150 mL/kg per day.10,11 Based on these data, the with mass transitions as m/z 331.1–m/z 313.3 estimated relative infant dose was calculated at 2.5%, for 11-OH-delta-9-tetrahydrocannabinol and m/z and the average absolute infant dose was estimated at 345.1–m/z 193.3 for 11-Nor-9-carboxy-delta-9- 8 micrograms per kilogram per day (Table 2). Area tetrahydrocannabinol. Our goal was to recruit 50 study under the breast milk concentration time curve from volunteers, but we were unable to recruit this number. zero to the time of the last sample was estimated by the linear trapezoidal rule. All these calculations RESULTS were done using Graphpad Prism 6. Figure 2 A total of eight women participated in the study. Four depicts the mean6SD concentrations of delta-9- of the participants indicated they used cannabis tetrahydrocannabinol in the breast milk. infrequently and one used cannabis seven to 10 times The results at zero hour were exceedingly low during the prior week. The preferred method of in six of eight participants (less than 2 ng/mL), consumption was smoking and the reported range of suggesting that most participants were able to abstain

VOL. 131, NO. 5, MAY 2018 Baker et al Inhaled Cannabis in Human Breast Milk 785

Copyright Ó by American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 1. Prestudy Self-Reported Cannabis Smoking

Patient No. Postpartum (Mo) Cannabis Use/Wk (No. of Times) Daily Cannabis Use (g) Method of Consumption

1 5 1 0.25 Inhalation 2ND 3 3 7–10 0.5–1 Inhalation 4 5 3–5 0.05 Inhalation 5 5 5 0.05 Inhalation 6ND 7 3 1–3 0.025 Inhalation 8ND ND, not disclosed. from using cannabis for 24 hours before the collection feeding medicine that drugs with high volumes of dis- of the samples. A relatively low but measurable tribution such as cannabis or propofol rapidly reach concentration of delta-9-tetrahydrocannabinol (5.8 clinically significant concentrations in the plasma and and 15.8 ng/mL) was found at zero time in two of central nervous system, but thereafter dissipate rap- the participants, which suggests some residual accu- idly as a result of redistribution into peripheral com- mulations of delta-9-tetrahydrocannabinol either from partments such as skeletal muscle or adipose tissue. prior heavy use or use close to the start of breast milk This invariably reduces the concentrations found in collection. Data obtained for five of eight individuals breast milk. are shown in Table 3 and graphed in Figure 3. We analyzed all samples for tetrahydrocannabi- Neither 11-OH delta-9-tetrahydrocannabinol nor nol metabolites 11-OH-delta-9-tetrahydrocannabinol 11-Nor-9-carboxy-delta-9-tetrahydrocannabinol, me- and 11-Nor-9-carboxy-delta-9-tetrahydrocannabinol. tabolites of delta-9-tetrahydrocannabinol, was quanti- These two metabolites were not detectable (with lower fiable in these samples because their concentrations limits of detection at 0.097 ng/mL) for two possible were below our limit of detection (0.097–3.15 ng/mL). reasons. One, the participants were instructed to stop using cannabis for 24 hours before the study; thus, DISCUSSION metabolites had dissipated. Two, our breast milk Our findings demonstrate breast milk concentrations samples were collected long before plasma concen- of delta-9-tetrahydrocannabinol peaked at 1 hour, trations of metabolites became evident. Thus, we did with a peak of 94 ng/mL (range 12.2–420.3 ng/mL), not find measureable concentrations of metabolites in and receded slowly over the subsequent 4 hours. breast milk within the 4 hours of this study. In Delta-9-tetrahydrocannabinol was transferred into addition, metabolites of delta-9-tetrahydrocannabinol mother’s milk such that an exclusively breastfeeding infant ingests an estimated 2.5% of the maternal dose Table 2. Pharmacokinetic Parameters of Delta-9- – (range 0.4 8.7%). Although the transfer of delta-9- Tetrahydrocannabinol in Human Breast tetrahydrocannabinol into the plasma compartment Milk Samples (N58) is almost instantaneous, the transfer of delta-9- tetrahydrocannabinol into breast milk in our study Calculated appears to be slightly slower than the transfer into Parameter (Units) Value* Median (Range) the plasma compartment. AUC (ng/h/mL) 213.9 110.5 (33.9–744.4) Numerous other studies with similar doses in Cavg (ng/mL) 53.5 27.6 (8.4–186.1) cigarette formulations suggest that plasma concentra- Cmax (ng/mL) 94 44.7 (12.2–420.3) tions in humans range as high as 94.3, 107.4, and Tmax (h) 1 1 (1–2) 155.1 ng/mL after smoking single cigarettes of 1.32%, Infant dose 8 4.1 (1.3–27.9) 12 (micrograms/kg/d) 1.97%, or 2.54% tetrahydrocannabinol, respectively. RID (%) 2.5 1.3 (0.4–8.7) Other studies reported plasma concentrations ranging AUC, area under the drug concentration time curve; C , average from 45.6 and 187.8 ng/mL and 76–267 ng/mL after avg drug concentration across the dose interval; Cmax, maximum 13,14 smoking of a single cigarette. It is believed rapid drug concentration across the dose interval; Tmax, time at which volatilization of delta-9-tetrahydrocannabinol leads to maximum concentration is observed; RID, relative infant dose for delta-9-tetrahydrocannabinol in milk. plasma concentrations rising even before the end of * Calculated value is obtained from the combined data at each the smoking session.15 It is well established in breast- time point for each parameter.

786 Baker et al Inhaled Cannabis in Human Breast Milk OBSTETRICS & GYNECOLOGY

Copyright Ó by American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. dose each mother received. Second, but more impor- tantly, we had access to the analytics for the product selected, which accurately quantified the percentage of delta-9-tetrahydrocannabinol (23.18%). Recruitment was challenging possibly as a result of the fact that women who use cannabis products and are pregnant or breastfeeding fear the legal ramifica- tions of being reported. Second, we asked women of their own volition to seek out the breast milk sample kits and to purchase the preselected product. This task was perhaps too onerous for some women. A significant limitation of this study was the lack of corresponding plasma samples for comparison, but Fig. 2. Mean concentration time profile of delta-9-tetrahy- at the same time, anonymity was necessary for the drocannabinol in human breast milk (mean6SD, n58). protection of the participants. Another weakness of Baker. Inhaled Cannabis in Human Breast Milk. Obstet Gynecol 2018. this study was that we were not able to verify consumption or sample pumping at the allotted times. We did encourage participants to have a partner are known to be more water-soluble and more polar available to 1) assure their infants’ welfare and 2) help than the parent drug. These two properties may make the participant stay as close to the specified timeline as it more difficult for metabolites to enter the breast possible. We believe that similarity between the val- milk compartment. ues obtained in the breast milk curve as well as that all The strength of our study was our attempt to eight participants peaked and cleared the delta-9- standardize the pharmacokinetic methodology for tetrahydrocannabinol in a period of 4 hours would detection of delta-9-tetrahydrocannabinol in breast suggest that most of participants did in fact abstain milk samples. It is clear that human breast milk is from cannabis use 24 hours before “zero time.” How- subject to change as a function of infant age, pre- ever, there remain many unanswered questions: 1) maturity, and volume. In women, 1–6 months post- What is the plasma level in the breastfeeding infant partum exclusively breastfeeding, regardless of weight that is exposed to cannabis products through human or body habitus, the breast milk compartment along breast milk? 2) What effect would repeated and con- with drug entry and exit remains fairly consistent.16 In tinuous doses have on breast milk concentrations? 3) our study, a single cannabis dispensary was chosen How much delta-9-tetrahydrocannabinol would trans- that was willing to set aside a certain preweighed stan- fer into a mother’s breast milk after the use of oral dardized product so that we could predetermine the cannabis products? 4) What do exogenous cannabis

Table 3. Drug Concentrations Observed Across the Dose Interval for Each Individual

Sample ID 12 345 678 Concentration (ng/mL)

Time (h) 0 ND ND ND ND 5.8 15.8 ND ND 0.33 7.0 11.1 16.3 12.3 47.1 115.8 8.2 23.4 1 11.3 34.8 47.2 5.9 115.8 420.2 19.3 97.3 2 17.3 42.2 28.5 12.2 95.2 193.3 27.8 83.5 4 9.2 21.7 10.7 4.7 67.2 43.0 24.2 24.4 AUC (ng/h/mL) 48.9 119.7 101.3 33.9 331.1 744.4 89.1 242.7 Cavg (ng/mL) 12.2 29.9 25.3 8.4 82.7 186.1 22.2 60.6 Cmax (ng/mL) 17.6 42.1 47.2 12.2 115.8 420.3 29.8 97.3 RID (%) 0.6 1.4 1.2 0.4 3.8 8.7 1.0 2.8

ND, not determined (below the level of detection); AUC, area under the drug concentration time curve; Cavg, average drug concentration across the dose interval; Cmax, maximum drug concentration across the dose interval; RID, relative infant dose for delta-9-tetrahydrocannabinol in milk.

VOL. 131, NO. 5, MAY 2018 Baker et al Inhaled Cannabis in Human Breast Milk 787

Copyright Ó by American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 3. Ranganathan M, D’Souza DC. The acute effects of cannabi- noids on memory in humans: a review. Psychopharmacology (Berl) 2006;188:425–44. 4. Day NL, Richardson GA. Prenatal marijuana use: epidemiol- ogy, methodologic issues, and infant outcome. Clin Perinatol 1991;18:77–91. 5. Fried PA. Marihuana use by pregnant women: neurobehavioral effects in neonates. Drug Alcohol Depend 1980;6:415–24. 6. Hofman A, Jaddoe VW, Mackenbach JP, Moll HA, Snijders RF, et al. Growth, development and health from early fetal life until young adulthood: the Generation R Study. Paediatr Peri- nat Epidemiol 2004;18:61–72. 7. Jutras-Aswad D, DiNieri JA, Harkany T, Hurd YL. Neurobio- logical consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome. Eur Arch Psy- chiatry Clin Neurosci 2009;259:395–412. 8. Gold M. The pharmacology of marijuana. In: Graham AW, Fig. 3. Illustrated graph of each patient’s data points (n58). Schultz T, editors. Principles of addiction medicine. Vol 1. Each color represents an individual. Chevy Chase (MD): American Society of Addiction Medicine; Baker. Inhaled Cannabis in Human Breast Milk. Obstet Gynecol 2018. 1998. 9. Perez-Reyes M, Wall ME. Presence of delta9- tetrahydrocannabinol in human milk. N Engl J Med 1982; products do to the endocannabinoid signaling system? 307:819–20. Finally, the most clinically significant question: 5) What 10. Bennett PN. Use of the monographs on drugs. In: Drugs and is the lasting effect of exposing developing infants to human lactation. 2nd ed. Amsterdam (The Netherlands): Elsev- ier; 1996. p. 442–3. cannabis? It remains unclear what exposure to canna- 11. Charles Czank LRM, Peter E. Hartmann. Human milk compo- bis products during this critical neurobehavioral devel- sition—fat. In: Hale TW, editor. Hale & Hartmann’s textbook of opment period will mean for the infant. These human lactation. 1st ed. Plano (TX): Hale Publishing; 2008. questions will require an enormous effort to determine. 12. Perez-Reyes M, Di Guiseppi S, Davis KH, Schindler VH, Cook Thus, larger scale investigations are warranted CE. Comparison of effects of marihuana cigarettes to three – and necessary to enable us to counsel women who different potencies. Clin Pharmacol Ther 1982;31:617 24. may be using cannabis medicinally or recreationally. 13. Perez-Reyes M, Owens SM, Di Guiseppi S. The clinical pharmacology and dynamics of marihuana cigarette smoking. J Clin Pharmacol 1981;21(suppl):201–7S. REFERENCES 14. Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization of the absorption phase of marijuana 1. Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R. Effects of smoking. Clin Pharmacol Ther 1992;52:31–41. cannabis on neurocognitive functioning: recent advances, neu- rodevelopmental influences, and sex differences. Neuropsychol 15. Huestis MA. Human cannabinoid pharmacokinetics. Chem Bi- Rev 2013;23:117–37. odivers 2007;4:1770–804. 2. Crean RD, Crane NA, Mason BJ. An evidence based review of 16. Cox DB, Owens RA, Hartmann PE. Blood and milk prolactin acute and long-term effects of cannabis use on executive cogni- and the rate of milk synthesis in women. Exp Physiol 1996;81: tive functions. J Addict Med 2011;5:1–8. 1007–20.

788 Baker et al Inhaled Cannabis in Human Breast Milk OBSTETRICS & GYNECOLOGY

Copyright Ó by American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.